chr5-14664847-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_138348.6(OTULIN):​c.22C>T​(p.Gln8Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

OTULIN
NM_138348.6 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.10
Variant links:
Genes affected
OTULIN (HGNC:25118): (OTU deubiquitinase with linear linkage specificity) This gene encodes a member of the peptidase C65 family of ubiquitin isopeptidases. Members of this family remove ubiquitin from proteins. The encoded enzyme specifically recognizes and removes M1(Met1)-linked, or linear, ubiquitin chains from protein substrates. Linear ubiquitin chains are known to regulate the NF-kappa B signaling pathway in the context of immunity and inflammation. Mutations in this gene cause a potentially fatal autoinflammatory syndrome in human patients. [provided by RefSeq, Sep 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-14664847-C-T is Pathogenic according to our data. Variant chr5-14664847-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1027708.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OTULINNM_138348.6 linkuse as main transcriptc.22C>T p.Gln8Ter stop_gained 1/7 ENST00000284274.5 NP_612357.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OTULINENST00000284274.5 linkuse as main transcriptc.22C>T p.Gln8Ter stop_gained 1/71 NM_138348.6 ENSP00000284274 P1
OTULINENST00000507335.1 linkuse as main transcriptn.116C>T non_coding_transcript_exon_variant 1/22
OTULINENST00000697367.1 linkuse as main transcriptc.22C>T p.Gln8Ter stop_gained, NMD_transcript_variant 1/5 ENSP00000513279
OTULINENST00000503023.2 linkuse as main transcriptc.22C>T p.Gln8Ter stop_gained, NMD_transcript_variant 1/65 ENSP00000427016

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1062644
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
504128
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Infantile-onset periodic fever-panniculitis-dermatosis syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 06, 2020This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Benign
0.53
D
MutationTaster
Benign
1.0
A
Vest4
0.092
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1735786455; hg19: chr5-14664956; API